Deep sequencing of genes in ethanol-metabolism pathway in alcoholism Alcohol dehydrogenases (ADHs) and aldehyde dehydrogenases (ALDHs) are in one of the most promising pathways being involved in the metabolism of ethanol and thus in the risk for alcoholism. The specific aims of the proposed study include: 1. To exhaustively search for variants in 7 ADH genes and 1 ALDH gene, including novel variants and rare variants, especially the potential functional variants, and then to make a complete bioinformatic map of variants of these genes. 2. (Main goal) To test associations between genetic variants (especially the replicable and functional SNVs, and rare variants) and alcohol dependence, confirm the functions of risk variants by cis-eQTL analysis, and then to determine the causal variants. Our long-term objectives in the future are to identify more causal loci and then confirm the functions of these loci using multiple research strategies. Eventually, these functional loci will serve as the targets for novel treatments on AD. We propose two steps in the research design to achieve these two specific aims. Step 1 (Aim 1) is a sequencing step: we will sequence 7 ADH genes and 1 ALDH gene in a European American and an African American case-control samples. Step 2 (Aim 2) is an association testing step: we will perform association tests in the above two samples (Step 1) using sequence data, to screen the variants for their potential associations with alcoholism. Then, in the testing step, the most promising variants for alcoholism identified in the screening step will be selected, genotyped and tested for their associations with alcoholism in two larger independent samples. This proposed project has a number of innovations. Its greatest significance is that it is very promising to identify the causa loci for alcoholism at these genes. Results are likely to have a significant impact on the understanding of the roles of ADH and ALDH genes in alcoholism, helping us to better understand the mechanism of the development of alcoholism. The findings will also be very helpful for the early- life prediction and prevention for alcoholism, for the development of biological markers for diagnosis of alcoholism, and for the improvement of the treatment for alcoholism. Finally, the expected findings will benefit public health.